DESCRIPTION (applicant?s abstract): Several characteristics of adeno-associated virus (AAV) such as lack 01 pathogenicity and site-specific integration make it a promising candidate for gene therapy applications. Of the six primate AAV serotypes (AAV 1-6), only AAV2 has been extensively studied and utilized in gene therapy application. A major limitation in the use of AAV2 for gene therapy is its broad host range. The long-term goal of this research is to generate recombinant AAV that will infect specific cell types without infecting others. To accomplish this, it is first necessary to identify and characterize the receptor binding domains of the different AAV serotypes. The primary objective of this proposal is to identify regions of the AAV serotype 1, 3, 4, and 5 capsids responsible for receptor binding. These goals will be accomplished by two aims: 1. to identify the regions of AAV serotypes 1, 3, 4, and 5 important in receptor binding by marker rescue of an AAV2 mutant deficient in receptor binding and 2. to identify the minimal receptor binding domains of AAV serotypes 4 and 5. Specific aim 2 is limited to serotypes 4 and 5 since they exhibit a tropism and bind to a receptor distinct from AAV2. Aim 2 will be accomplished by mutation of the regions identified in aim 1 and by screening the resultant mutants for the ability to produce capsids, package DNA, and infect cells.